The tolerance of critical normal tissues is often dose limiting in clinical radiotherapy. Tolerance doses are only relatively well known for conventional fractionation schemes. With the use of higher doses per fraction (3 Gy or more), more severe late complications occurred as was predicted on basis of acute effects. Decreasing the fractional doses below the conventional dose of 2 Gy resulted in a greater increase in tolerance for late effects as for acute effects. These observations provide a basis for an improvement of cancer therapy by, e.g., multiple daily fractionation. However, before any new treatment scheme can be implemented in the clinic, quantitative information should be available on the tolerance of critical normal tissues, such as the central nervous system (CNS). Experimental studies on time-dose relationships in the rat spinal cord have shown an excellent correlation with observations in the human CNS. Similar to the human brain, early (6 months) and late (8-18 months) waves of delayed damage have been observed in the rat cervical spinal cord, both of which are clinically relevant. The repair and regeneration characteristics of the target cells involved are different, but both show a large capacity for repair of subeffective radiation damage. The development of these well-defined endpoints will be studied on the following aspects: a) effect of decreasing fraction-size on the total effective dose, b) the kinetics of repair of sublethal damage as a function of fraction size, c) long-term recovery of residual damage, and d) dependence of the effective dose on the irradiated volume.